OBJECTIVE: Six per cent of hospital patients experience a patient safety incident, of which 12% result in severe/fatal outcomes. Acutely sick patients are at heightened risk. Our aim was to identify the most frequently reported incidents in acute medical units and their characteristics. DESIGN: Retrospective mixed methods methodology: (1) an a priori coding process, applying a multi-axial coding framework to incident reports; and, (2) a thematic interpretative analysis of reports. SETTING: Patient safety incident reports (10 years, 2005-2015) collected from the National Reporting and Learning System, which receives reports from hospitals and other care settings across England and Wales. PARTICIPANTS: Reports describing severe harm/death in acute medical unit were identified. MAIN OUTCOME MEASURES: Incident type, contributory factors, outcomes and level of harm were identified in the included reports. During thematic analysis, themes and metathemes were synthesised to inform priorities for quality improvement. RESULTS: A total of 377 reports of severe harm or death were confirmed. The most common incident types were diagnostic errors (n = 79), medication-related errors (n = 61), and failures monitoring patients (n = 57). Incidents commonly stemmed from lack of active decision-making during patient admissions and communication failures between teams. Patients were at heightened risk of unsafe care during handovers and transfers of care. Metathemes included the necessity of patient self-advocacy and a lack of care coordination. CONCLUSION: This 10-year national analysis of incident reports provides recommendations to improve patient safety including: introduction of electronic prescribing and monitoring systems; forcing checklists to reduce diagnostic errors; and increased senior presence overnight and at weekends.